Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice
II3NeuAc-GgOse4Cer (GM1) gangliosidosis is an incurable lysosomal storage disease caused by a deficiency in acid β-galactosidase (β-gal), resulting in the accumulation of ganglioside GM1 and its asialo derivative GgOse4Cer (GA1) in the central nervous system, primarily in the brain. In this study, w...
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| Format: | Article |
| Language: | English |
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Elsevier
2005-04-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520340098 |
| _version_ | 1818728226021703680 |
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| author | J.L. Kasperzyk A. d'Azzo F.M. Platt J. Alroy T.N. Seyfried |
| author_facet | J.L. Kasperzyk A. d'Azzo F.M. Platt J. Alroy T.N. Seyfried |
| author_sort | J.L. Kasperzyk |
| collection | DOAJ |
| description | II3NeuAc-GgOse4Cer (GM1) gangliosidosis is an incurable lysosomal storage disease caused by a deficiency in acid β-galactosidase (β-gal), resulting in the accumulation of ganglioside GM1 and its asialo derivative GgOse4Cer (GA1) in the central nervous system, primarily in the brain. In this study, we investigated the effects of N-butyldeoxygalacto-nojirimycin (N B-DGJ), an imino sugar that inhibits ganglioside biosynthesis, in normal C57BL/6J mice and in β-gal knockout (β-gal−/−) mice from postnatal day 9 (p-9) to p-15. This is a period of active cerebellar development and central nervous system (CNS) myelinogenesis in the mouse and would be comparable to late-stage embryonic and early neonatal development in humans. N B-DGJ significantly reduced total ganglioside and GM1 content in cerebrum-brainstem (C-BS) and in cerebellum of normal and β-gal−/− mice. N B-DGJ had no adverse effects on body weight or C-BS/cerebellar weight, water content, or thickness of the external cerebellar granule cell layer. Sphingomyelin was increased in C-BS and cerebellum, but no changes were found for cerebroside (a myelin-enriched glycosphingolipid), neutral phospholipids, or GA1 in the treated mice.Our findings indicate that the effects of N B-DGJ in the postnatal CNS are largely specific to gangliosides and suggest that N B-DGJ may be an effective early intervention therapy for GM1 gangliosidosis and other ganglioside storage disorders. |
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| format | Article |
| id | doaj.art-ca0629307d7343c7a4295dffd03ffc5c |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T22:26:37Z |
| publishDate | 2005-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-ca0629307d7343c7a4295dffd03ffc5c2022-12-21T21:30:19ZengElsevierJournal of Lipid Research0022-22752005-04-01464744751Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis miceJ.L. Kasperzyk0A. d'Azzo1F.M. Platt2J. Alroy3T.N. Seyfried4Department of Biology, Boston College, Chestnut Hill, MA 02467Department of Biology, Boston College, Chestnut Hill, MA 02467Department of Biology, Boston College, Chestnut Hill, MA 02467Department of Biology, Boston College, Chestnut Hill, MA 02467Department of Biology, Boston College, Chestnut Hill, MA 02467II3NeuAc-GgOse4Cer (GM1) gangliosidosis is an incurable lysosomal storage disease caused by a deficiency in acid β-galactosidase (β-gal), resulting in the accumulation of ganglioside GM1 and its asialo derivative GgOse4Cer (GA1) in the central nervous system, primarily in the brain. In this study, we investigated the effects of N-butyldeoxygalacto-nojirimycin (N B-DGJ), an imino sugar that inhibits ganglioside biosynthesis, in normal C57BL/6J mice and in β-gal knockout (β-gal−/−) mice from postnatal day 9 (p-9) to p-15. This is a period of active cerebellar development and central nervous system (CNS) myelinogenesis in the mouse and would be comparable to late-stage embryonic and early neonatal development in humans. N B-DGJ significantly reduced total ganglioside and GM1 content in cerebrum-brainstem (C-BS) and in cerebellum of normal and β-gal−/− mice. N B-DGJ had no adverse effects on body weight or C-BS/cerebellar weight, water content, or thickness of the external cerebellar granule cell layer. Sphingomyelin was increased in C-BS and cerebellum, but no changes were found for cerebroside (a myelin-enriched glycosphingolipid), neutral phospholipids, or GA1 in the treated mice.Our findings indicate that the effects of N B-DGJ in the postnatal CNS are largely specific to gangliosides and suggest that N B-DGJ may be an effective early intervention therapy for GM1 gangliosidosis and other ganglioside storage disorders.http://www.sciencedirect.com/science/article/pii/S0022227520340098N-butyldeoxygalactonojirimycinII3 (NeuAc)2-LacCerII3NeuAc-GgOse4Cerasialo derivativemyelincerebrosides |
| spellingShingle | J.L. Kasperzyk A. d'Azzo F.M. Platt J. Alroy T.N. Seyfried Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice Journal of Lipid Research N-butyldeoxygalactonojirimycin II3 (NeuAc)2-LacCer II3NeuAc-GgOse4Cer asialo derivative myelin cerebrosides |
| title | Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice |
| title_full | Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice |
| title_fullStr | Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice |
| title_full_unstemmed | Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice |
| title_short | Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice |
| title_sort | substrate reduction reduces gangliosides in postnatal cerebrum brainstem and cerebellum in gm1 gangliosidosis mice |
| topic | N-butyldeoxygalactonojirimycin II3 (NeuAc)2-LacCer II3NeuAc-GgOse4Cer asialo derivative myelin cerebrosides |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520340098 |
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